title: 1,3-Dialkyl-8-(hetero)aryl-9-OH-9-deazaxanthines as potent A2B adenosine receptor antagonists: design, synthesis, structure-affinity and structure-selectivity relationships.
abstract: A number of 1,3-dialkyl-8-(hetero)aryl-9-OH-9-deazaxanthines were prepared and evaluated as ligands of recombinant human adenosine receptors (hARs). Several 1,3-dipropyl derivatives endowed with nanomolar binding affinity at hA(2B) receptors, but poor selectivity over hA(2A), hA(1) and hA(3) AR subtypes were identified. A comparison with the corresponding 7-OH- and 7,9-unsubstituted-deazaxanthines revealed that 9-OH-9-deazaxanthines are more potent hA(2B) ligands with lower partition coefficients and higher water solubility compared to the other two congeneric classes of deazaxanthines. An optimization of the para-substituent of the 8-phenyl ring of 9-OH-9-deazaxanthines led to the discovery of compound 38, which exhibited outstanding hA(2B) affinity (Ki=1.0 nM), good selectivity over hA(2A), hA(1) and hA(3) (selectivity indices=100, 79 and 1290, respectively) and excellent antagonist potency in a functional assay on rat A(2B) (pA(2B)=9.33).
authors.affiliation: Dipartimento Farmaco-chimico, Università degli Studi di Bari, via Orabona 4, I-70125 Bari, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Stefanachi
authors.forename: Orazio
authors.initials: O
authors.lastname: Nicolotti
authors.forename: Francesco
authors.initials: F
authors.lastname: Leonetti
authors.forename: Saverio
authors.initials: S
authors.lastname: Cellamare
authors.forename: Francesco
authors.initials: F
authors.lastname: Campagna
authors.forename: Maria Isabel
authors.initials: MI
authors.lastname: Loza
authors.forename: Jose Manuel
authors.initials: JM
authors.lastname: Brea
authors.forename: Fernando
authors.initials: F
authors.lastname: Mazza
authors.forename: Enrico
authors.initials: E
authors.lastname: Gavuzzo
authors.forename: Angelo
authors.initials: A
authors.lastname: Carotti
mesh_terms: D058917:Adenosine A2 Receptor Antagonists; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D051381:Rats; D043704:Receptor, Adenosine A2B / Q000378:metabolism; D013329:Structure-Activity Relationship; D014970:Xanthines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D058917:Adenosine A2 Receptor Antagonists; D043704:Receptor, Adenosine A2B; D014970:Xanthines